@article{b7c68fe95df74ad5b2d52707bb2a6a47,
title = "A validation of models for prediction of pathogenic variants in mismatch repair genes",
abstract = "Purpose: Models used to predict the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, are widely used. Recently, MMRpro was updated with new colorectal cancer penetrance estimates. The purpose of this study was to evaluate the predictive performance of MMRpro and other models for individuals with a family history of colorectal cancer. Methods: We performed a validation study of 4 models, Leiden, MMRpredict, PREMM5, and MMRpro, using 784 members of clinic-based families from the United States. Predicted probabilities were compared with germline testing results and evaluated for discrimination, calibration, and predictive accuracy. We analyzed several strategies to combine models and improve predictive performance. Results: MMRpro with additional tumor information (MMRpro+) and PREMM5 outperformed the other models in discrimination and predictive accuracy. MMRpro+ was the best calibrated with an observed to expected ratio of 0.98 (95\% CI = 0.89-1.08). The combination models showed improvement over PREMM5 and performed similar to MMRpro+. Conclusion: MMRpro+ and PREMM5 performed well in predicting the probability of having a pathogenic homozygous or heterozygous variant in a mismatch repair gene. They serve as useful clinical decision tools for identifying individuals who would benefit greatly from screening and prevention strategies.",
keywords = "Colorectal cancer, Lynch syndrome, Mismatch repair, Model combination, Model validation",
author = "Cathy Shyr and Blackford, \{Amanda L.\} and Theodore Huang and Jianfeng Ke and Nofal Ouardaoui and Lorenzo Trippa and Sapna Syngal and Chinedu Ukaegbu and Hajime Uno and Khedoudja Nafa and Stadler, \{Zsofia K.\} and Kenneth Offit and Amos, \{Christopher I.\} and Lynch, \{Patrick M.\} and Sining Chen and Giardiello, \{Francis M.\} and Buchanan, \{Daniel D.\} and Hopper, \{John L.\} and Jenkins, \{Mark A.\} and Southey, \{Melissa C.\} and Win, \{Aung Ko\} and Figueiredo, \{Jane C.\} and Danielle Braun and Giovanni Parmigiani",
note = "Funding Information: This work was supported by National Institutes of Health, United States grants 5P50CA062924-20 (F.M.G. and G.P.), 5P30CA006516-54 (G.P.), T32CA009001 (T.H.), 5T32CA009337-40 (C.S.), and R01 CA132829 (S.S.). The Colon Cancer Family Registry (Colon CFR , www.coloncfr.org ) is supported in part by funding from the National Cancer Institute, United States , National Institutes of Health (award U01 CA167551). Support for case ascertainment was provided in part from the Surveillance, Epidemiology, and End Results (SEER) Program and the following US state cancer registries: Arizona, Colorado, Minnesota, North Carolina, New Hampshire and by the Victoria Cancer Registry (Australia) and Ontario Cancer Registry (Canada). Funding Information: We thank late Henry Lynch for his leadership in the creation of the Creighton University familial registry and his willingness to share data for this project. This work was supported by National Institutes of Health, United States grants 5P50CA062924-20 (F.M.G. and G.P.), 5P30CA006516-54 (G.P.), T32CA009001 (T.H.), 5T32CA009337-40 (C.S.), and R01 CA132829 (S.S.). The Colon Cancer Family Registry (Colon CFR, www.coloncfr.org) is supported in part by funding from the National Cancer Institute, United States, National Institutes of Health (award U01 CA167551). Support for case ascertainment was provided in part from the Surveillance, Epidemiology, and End Results (SEER) Program and the following US state cancer registries: Arizona, Colorado, Minnesota, North Carolina, New Hampshire and by the Victoria Cancer Registry (Australia) and Ontario Cancer Registry (Canada). The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Conceptualization: G.P. D.B.; Data Curation: G.P. A.L.B. N.O. S.S. K.O. P.M.L. F.M.G. M.A.J. J.C.F. C.I.A. J.L.H. A.K.W. Z.K.S. M.C.S. C.U.; Formal Analysis: C.S. A.L.B. T.H.; Methodology: C.S. A.L.B. T.H. J.K. H.U. L.T. S.C. D.B.; Software: G.P. D.B. A.L.B. S.C. C.S. T.H.; Supervision: G.P. D.B.; Validation: G.P. D.B. C.S. A.L.B. T.H.; Writing-original draft: C.S. A.L.B. G.P. S.C. D.B.; Writing-review and editing: C.S. A.L.B. T.H. J.K. N.O. L.T. S.S. C.U. H.U. K.N. Z.K.S. K.O. C.I.A. P.M.L, S.C. F.M.G. D.D.B. J.L.H. M.A.J. M.C.S. A.K.W. J.C.F. D.B. G.P. The Dana-Farber Cancer Institute Institutional Review Board determined that this work is not research involving human subjects as defined by Department Of Health And Human Services and US Food and Drug Administration regulations. Institutional Review Board review and approval by this organization is not required. The data used in this study were de-identified. Publisher Copyright: {\textcopyright} 2022 American College of Medical Genetics and Genomics",
year = "2022",
month = oct,
doi = "10.1016/j.gim.2022.07.004",
language = "English",
volume = "24",
pages = "2155--2166",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Nature Publishing Group",
number = "10",
}
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